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Talanta 72 (2007) 13–27

Review

Optical sensors and biosensors based on sol–gel films

Paula C.A. Jeronimo, Alberto N. Araujo ∗, M. Conceicao B.S.M. MontenegroREQUIMTE – Dpt. Physical-Chemistry, Faculty of Pharmacy, University of Porto, R. Anıbal Cunha 164, 4099-030 Porto, Portugal

Received 26 April 2006; received in revised form 6 September 2006; accepted 27 September 2006Available online 27 October 2006

bstract

The sol–gel technology is being increasingly used for the development of optical sensors and biosensors, due to its simplicity and versatility. By

his process, porous thin films incorporating different chemical and biochemical sensing agents are easily obtained at room temperature, allowingnal structures with mechanical and thermal stability as well as good optical characteristics. In this article, an overview of the state-of-the-artf sol–gel thin films-based optical sensors is presented. Applications reviewed include sensors for determination of pH, gases, ionic species andolvents, as well as biosensors.

2006 Elsevier B.V. All rights reserved.

eywords: Optical sensors; Biosensors; Sol–gel technology; Films

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131.1. Optical fibre chemical sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131.2. The sol–gel process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2. Chemical optical sensors: applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.1. pH sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.2. Gas sensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172.3. Sensors for ionic species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192.4. Sensors for determination of solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212.5. Other applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

3. Sol–gel films based optical biosensors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224. Conclusions and trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

. Introduction

.1. Optical fibre chemical sensors

A chemical sensor is a device capable of providing contin-ous real-time chemical information about a sample of interest1]. Optical sensors, or optrodes, represent a group of chemicalensors in which electromagnetic radiation is used to generate

the analytical signal in a transduction element. These sensors canbe based on various optical principles (absorbance, reflectance,luminescence, fluorescence), covering different regions of thespectra (UV, visible, IR, NIR) and allowing the measurement notonly of the intensity of light, but also of other related properties,such as refractive index, scattering, diffraction and polarization.

Optical fibres are commonly employed in this type ofsensors to transmit the electromagnetic radiation to and from

∗ Corresponding author. Tel.: +351 222078940; fax: +351 222004427.E-mail address: anaraujo@ff.up.pt (A.N. Araujo).

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039-9140/$ – see front matter © 2006 Elsevier B.V. All rights reserved.oi:10.1016/j.talanta.2006.09.029

sensing region that is in direct contact with the sample.esides the advantages in terms of cheapness and ease ofiniaturization, a wide variety of sensor designs are made

ossible [2]. The most common are distal-type sensors, in

14 P.C.A. Jeronimo et al. / Talanta 72 (2007) 13–27

Fig. 1. Typical configurations of optical fibre chemical sensors. A and B are extrinsic type sensors, in which the fibre is used to direct light; C and D are intrinsics the fibt ed to

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ensors, in which the sensor phase modifies the transmission characteristics ofhe side (C); part of the cladding can be removed and leave the fibre core expos

hich the indicator chemistry is immobilized at the tip of aingle or bifurcated optical fibre. Alternatively, the sensinghemistry can be immobilized along a section of the core of theptical fibre to make an evanescent field sensor. Two sensingonfigurations are easily recognized: the extrinsic mode usesptical fibres to direct the electromagnetic radiation to theample, and later to the detector; the intrinsic mode employs thebre itself as transduction element. The interaction of light with

he sample takes place inside the guiding region, or in the lowerefractive index surrounding medium (evanescent field). Theasic designs of optical fibre sensors are shown schematically inig. 1.

In most optical sensors, the chemical transducer consists ofmmobilized chemical reagents, placed in the sensing region ofhe optical fibre either by direct deposition or by encapsula-

ion in a polymeric matrix. The choice of the polymer support

ay influence the performance of the sensor, namely its selec-ivity and response time, and is governed by parameters like

echanical stability, permeability to the analyte and suitability

rR

S

re. The sensor membrane can be placed on the tip of the fibre (A and B) or onthe chemical interaction medium (D).

or reagent immobilization. Porous glass-like materials obtainedy the sol–gel method present several properties that make themttractive for use in optical chemical sensing applications [3–5].n particular, sol–gel thin films are now widely recognized as aromising strategy for the effective and low cost mass produc-ion of reversible, robust and portable optical chemical sensorsnd biosensors.

.2. The sol–gel process

The sol–gel technology [6] is considered one of the fastestrowing fields of contemporary chemistry. It offers a low tem-erature alternative to conventional glass production, enablingnal products with high homogeneity and purity. Consideringilica alkoxydes as starting materials, the sol–gel process can be

epresented by the following global chemical equation, in which

is an alkyl group:

i(OR)4 + (4 − x)H2O → SiOx(OH)4−2x + 4ROH (1)

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The reaction takes place through hydrolysis (2) and conden-ation (3) of monomeric alkoxysilanes:

Si OR + H2O → Si OH + ROH (2)

Si OR + HO Si → Si O Si + ROH (3)

The most frequently used precursors are tetramethoxysilaneTMOS) and tetraethoxysilane (TEOS). In the typical proce-ure, the precursor is mixed with water and a co-solvent (usuallythanol or methanol), yielding a homogeneous sol. Hydroly-is and polycondensation can be accelerated by employing anppropriate acid or base catalyst. As the reactions proceed, grad-al increase of the solution’s viscosity occurs and a rigid, porous,nterconnected gel is formed. After aging and drying at roomemperature, a xerogel is obtained, which may be further densi-ed at high temperatures if a non-porous glass is intended. Thehysico-chemical properties of the obtained gel depend on thearameters of the process. Factors such as the type of precur-or, the pH, the nature and concentration of the catalyst, H2O:Siolar ratio (R), the type of co-solvent, temperature, method and

xtension of drying, the presence of doping substances, or evenhe chemical nature of the gelation vessel, may have a strongnfluence on the sol–gel glass characteristics: porosity, surfacerea, refractive index, thickness and mechanical properties. Inrder to obtain sensing devices, the chemical or biological rec-gnizing elements can be added to the sol during different stepsf the process, remaining firmly retained in the matrix, yet ster-cally accessible to small molecules and ions that may diffusento the porous structure.

The mild conditions of the process, together with the chem-cal inertia of sol–gel glass, make these materials ideal forhe immobilization of numerous organic, organometallic andiological molecules. Characteristics such as polarity, poros-ty and ion exchange capacity can be easily tailored by simple

odification of the polymerisation protocol. Sol–gel porousatrices in general are thermally and mechanically stable, do

ot photodegrade and can be transparent to wavelengths above50 nm, which makes them highly suitable for optical applica-ions. Sol–gel glasses can be obtained in a variety of shapes andonfigurations (thin films, fibres, monoliths, powders, etc.) anday be easily miniaturized and attached to most other materials.Thin films (with thickness usually < 1 �m) are obtained by

eans of spin-coating, dip-coating or spray-coating techniques7]. They are regarded as the most technologically importantol–gel configuration, representing a key area for the devel-pment of optical sensors. Thin films and coatings requirenly small amounts of precursors and embedded functionalolecules, exhibit fast response times and superior transparency,

ossess mechanical resistance and are less susceptible to crackhan monoliths (particularly when exposed to liquids). Sol–geloatings can also be easily combined with optical fibres or pla-ar waveguides, providing intrinsic evanescent wave sensors;urthermore, thin films have great potential for miniaturisation

nd also permit the possibility of preparing multi-layer config-rations.

In this paper we present an overview of the state-of-the-rt of sol–gel thin films-based optical sensors. Sensing devices

tbaw

nta 72 (2007) 13–27 15

eported in the literature until the present moment were dividedccording to their main application: sensors for determinationf pH, gases, ionic species and solvents, as well as other lessxplored purposes, are described. Finally, special attention isevoted to optical biosensors: this field has been experiencingrapid growth, as a reflex of the increasing demand for stable,

obust and specific devices for application in areas such as foodndustry, diagnostics, in vivo monitoring, environmental controlnd biotechnology.

. Chemical optical sensors: applications

.1. pH sensors

To date, most of the reported sol–gel based optical sensorsre related with the measurement of pH, as a consequence ofhe wide availability of pH-sensitive dyes and the fast diffusionf protons through the sol–gel porous glass. Optical pH sensorsan offer significant advantages over commercially available pHlectrodes, since electromagnetic interference on the optical sig-al can be easily overcome, and thus superior signal to noise ratios obtained. Although typically responding to narrower pH inter-als, pH optical sensors usually possess long lasting lifetime.hey also exhibit reversible and fast response, durability, lowost, safety, ease of miniaturisation and mechanical robustness.hese sensing devices are obtained by simply incorporatingpH indicator into the sol–gel matrix, and their characteriza-

ion is quite straightforward [8]. Several pH sensitive dyes haveeen immobilized in sol–gel thin films for attainment of conven-ional non-waveguided optical sensors, based on fluorescence orbsorbance measurements (Table 1).

The easiness by which sol–gel films can be combined withptical fibres and waveguides has led to the development ofntrinsic pH sensors, summarized in Table 2. Because thenterrogating light remains guided, considerable miniaturisations achievable, which is advantageous when biological assaysr in situ remote monitoring are intended; additionally, opti-al transparency of the sample is not mandatory when theol–gel/evanescent wave approach is employed. As can be seenn Table 2, most optical fibre-based pH sensors exhibit enlargedesponse intervals, when compared with the conventional ones,nd response times are also typically shorter. For example, theptical fibre sensor proposed by Suah et al. [29], based on bro-ophenol blue doped sol–gel coatings and relying on artificial

eural network for signal processing, presented a dynamic rangef 2.0–12.0 pH units, instead of 3.0–5.0 units for the same indica-or in solution, and response time of 15–150 s (depending on theH and amount of immobilized dye). By associating sol–gel lay-rs with optical fibres, in vivo determinations in which the sensorust be sterilized before use (for example, in a steam auto-

lave) are also facilitated. The miniaturised pH sensor developedy McCulloch and Uttamchandani [32], obtained by coating auorescein-doped sol–gel film on a submicrometre optical fibre

ip, is a good example, and it was applied to pH monitoring iniological media. The optical fibre pH sensor proposed by Grantnd Glass [37], based on sol–gel encapsulation of SNARF-1C,as developed specifically for local blood pH measurements,

16 P.C.A. Jeronimo et al. / Talanta 72 (2007) 13–27

Table 1Conventional pH optical sensors based on pH indicators immobilized in sol–gel thin films

pH indicator Sol–gel precursors pH range Response time Lifetime/stability Principle of detection Ref.

Aminofluorescein TMOS 4.0–9.0 90 s 6 months (stored indistilled water)

Fluorescence [9]

10-(4-Aminophenyl)-5,15-dimesitylcorrole

TEOS 2.7–10.30 <120 s 1 month Fluorescence [10]

Bromocresol green TEOS + MTESa 7.0–10.0 106 s – Absorption [11]Bromocresol green TEOS + MTMS/

BTMS/PTMS5.0–8.0 <60 s 1–2 weeks Absorption [12]

Carboxyfluorosceinb TMOS 6.0–7.5 <1 s – Fluorescence [13]Cresol red TEOS + MTMS/

BTMS/PTMS7.0–11.0 <60 s 1–2 weeks Absorption [12]

Dimethyl yellow TEOS + MTES 2.9–4.0 200 s (neutral to acid) 17 h (continuousimmersion)

Absorption [14]

2000 s (acid to neutral)DPO TEOS 3.0–7.0 4.5 min <3 months Fluorescence [15]Eriochrome cyanine TMOS 6.0–8.0; 10.0–12.0 – 20 h Luminescence [16]Europium + terbium complexes TMOS 6.0–8.0 100 s – Luminescence [17]Europium complex + BTB TMOS 5.0–9.0 100 s 5 h (continuous use) Luminescence/fluorescence [18]

2 months (stored)Methyl red TMOS 6.7–10.0 – – Absorption [19]Methyl redc TEOS 8.0–14.0 1 min – Absorption [20]Phenol red TEOS + PTES 6.0–12.0 <20 s 12 months Absorption [21]Ruthenium(II)polypyridyl TEOS 3.0–9.0 – Several months Fluorescente [22]TRH + bromothymol blue TEOS – – Several days Fluorescence [23]

BTMS: Isobutyltrimethoxysilane; DPO: 4-(p-N,N-dimethylaminophenylmethylene)-2-phenyl-5-oxazolone; MTES: methyltriethoxysilane; MTMS:methyltrimethoxysilane; PTES: phenyltriethoxysilane; PTMS: phenyltrimethoxysilane; TRH: Texas Red Hydrazide.

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a Alkali post-fabrication treatment of the films’ surface.b Pre-encapsulated in liposomes.c Applied to the monitoring of environmental acidity, in liquid and gas phase

s part of a catheter-based array of sensors to monitor strokeatients.

Another approach for accomplishing sensors with linearesponse over a broad pH range, simple calibration, as well as

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able 2ntrinsic pH sensors based on doped sol–gel films combined with optical fibres

H indicator Sol–gel precursors/additives pH range Response t

romocresol purple MTES 4.5–8.2 <15 sromophenol blue TEOS 3.0–6.0 2 sromophenol blue TEOS + MTES 3.0–8.0 20–40 sromophenol blue TEOS 4.0–7.5 5 sromophenol blue TEOS + Triton X-100 2.0–12.0 15–150 sromophenol blue TEOS 5.0–7.0 10 sresol red TEOS 6.5–11.0 5 sluorescein TEOS 4.0–8.0 –luorescein TEOS 3.0–10.0 msluorescein a 7.0–11.0 –luorescein (FITC) TEOS + APTES + PDMS

(basic catalysis)4.5–8.0 1.1 ± 0.3 s

(increasing3.5 ± 0.3 s(decreasing

PTS TEOS + APTES + PDMS(basic catalysis)

6.0–8.5 13.4 ± 2.4

-Naphtholphthalein TMOS + CTAB 4.0–11.0 minhenol red TEOS 7.5–11.5 5 sNARF-1C TMOS 6.8–8.0 <15 shymol blue TEOS 8.0–12.0 5 s

PTES: 3-Aminopropyltriethoxysilane; ATR: attenuated total reflection; CTAB: cetyltpyrenetrisulfonic acid; PDMS: polydimethylsiloxane; SNARF-1C: seminaphthorhoa Not specified.

onstant sensitivity and precision in the whole response inter-al, is to use mixtures of multiple pH indicators immobilizedn the same sol–gel layer [39–42]; a fibre optic sensing deviceased on overlapped multiple sol–gel coatings doped with a pH

ime Lifetime/stability Principle of detection Ref.

2 days Absorption (ATR) [24]12 months (stored ambient air) Absorption (ATR) [25]– Absorption [26,27]– Absorption [28]– Absorption [29]– Transmittance [30]– Absorption [28]– Fluorescence [31]– Fluorescence [32]<1 week Fluorescence [33]

pH)2 months (stored at pH 2.5) Fluorescence [34]

)s 12 months Fluorescence [35]

– Absorption [36]– Absorption [28]3 days (continuous use) Fluorescence [37]– Absorption [38]

rimethylammonium bromide; FITC: fluorescein isothiocyanate: HPTS: hydrox-damine-1 carboxylate.

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P.C.A. Jeronimo et al.

ndicator has also been proposed [43], presenting an increase inensitivity of 70%.

The entrapment of acid–base indicators in silica thin filmsbtained by the sol–gel method has also been used for the con-truction of optical sensors designed particularly for high acidityeasurements. These sensors find application in many indus-

rial processes that involve concentrated strong acids, highlyollutant and corrosive, and are proposed as reliable and inex-ensive alternatives to classical titration procedures. Allain et al.44] used sol–gel films doped with bromocresol purple castedn the surface of Pyrex glass slides for the determination ofCl in a wide range of concentrations (1–11 M), with short

esponse time (1 s). Noire et al. [45,46] developed an evanes-ent wave optical sensor for monitoring of HNO3 (1–10 M) inuclear fuel reprocessing systems, based on the immobiliza-ion of chromoxane cyanine R in sol–gel membranes coated onhe core of unclad optical fibres. Shamsipur and Azimi [47]ntrapped the dyes rhodamine B and safranine T in sol–gelorous films, for the determination of HCl and HNO3 betweenand 9 M. An optical sensor obtained by immobilization of

henol red in organically modified sol–gel films (TEOS co-olymerised with phenyltriethoxysilane) was proposed by Wangt al. [48] for monitoring of HCl in solution and/or gas. Thisensing device displayed detection limit to moistured gaseousCl below 12 ppm, linear response to HCl in solution in the

nterval 0.01–6 M HCl, response time of 40 s and lifetime ofore than 1 year. Recently, Carmona et al. [49] demonstrated

he application of these sensing devices to environmental acidityonitoring, as an important tool in the preventive conservation

f historical objects. Optical sensors prepared by immobilizationf chlorophenol red in sol–gel films were applied to the detec-ion of pH atmospheric changes, as well as SO2 concentrations atbout 10 ppm. Garcia-Heras et al. [50] encapsulated the indicator-[4-(dimethylamino)phenylazo]benzoic acid in porous sol–gellms, and the sensor obtained was used for monitoring air acidity

n downtown Cracow, Poland. The sensor’s detection thresholdas found to be 10 �g m−3 of SO2, which corresponded with

n estimated pH precision of 0.05. The response was obtainedfter 1 day of exposure.

Some sol–gel films-based pH sensors have also been appliedo ammonia monitoring. Lobnik and Wolfbeis [51] developedn optical sensor for the continuous determination of dissolvedmmonia, by incorporating aminofluorescein in organicallyodified sol–gel films prepared by co-polymerisation of TMOS

nd diphenyldimethoxysilane. The dynamic range was from 1o 20 ppm and storage stability (in distilled water) was over 6

onths. Malins et al. [52] proposed a compact planar waveguidemmonia sensor for personal monitoring tasks in industrialnvironments, based on a cyanine dye doped sol–gel film;his sensor was fully reversible, presented limit of detectionf 5 ppm and response time of a few seconds. MacCraith ando-workers [53] and, more recently, Cao and Duan [54] as wells Tao et al. [55], used sol–gel films doped with bromocresol

urple and coated on unclad optical fibres for detecting gaseousmmonia. The reported results demonstrated that low cost,ensitive and fast response evanescent wave sensors could bettained.

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nta 72 (2007) 13–27 17

.2. Gas sensors

Optical sensors for determination of oxygen and other gasesre considered more attractive than conventional amperometricevices because they are typically fast, low cost and not eas-ly poisoned by sample constituents. The use of sol–gel filmsor development of optical gas sensors is becoming increasinglymportant, as reflected by the significant number of sensing sys-ems reported in the literature [56–86], summarized in Table 3,nd even by commercially available devices [87].

Nanocomposites with sensoring function have been recentlyroposed as a new area of interest in the field of optical gasensors. The electrical resistance or optical transmittance ofhese materials is changed due to variations of the free elec-ron density as a consequence of physisorption, chemisorptionnd catalytic reactions of the analyte gas and the surface ofhe material; since the electrical response to different gases is

surface related phenomenon, the large specific surface areaf sol–gel films should enhance the sensor response. Martuccit al. [56,57] prepared SiO2–NiO and SiO2–Co3O4 nanocom-osite films using the sol–gel method. The nanoporosity of theol–gel matrix provided a path for gas molecules to reach theunctional particles embedded, and the films showed a reversiblehange in resistance to different gases like CO and H2, as wells a reversible change in the optical transmittance in the vis-IR range when exposed to CO, providing detection limits of

pproximately 10 ppm.Optical sensors for determination of carbon dioxide play an

mportant role in several environmental, industrial and biolog-cal processes, where detection limit and moisture insensitivityequirements are often to be considered. Typically, the devel-pment of CO2 sensors is based upon the immobilization ofuorescent or colorimetric pH indicators, which can be used for

he detection of the gas in environments where potential inter-erence from other acidic or basic species is negligible. Malinsnd MacCraith [58] incorporated the deprotonated form of theuorescent reagent pyranine in an organically modified sol–gellm by means of a phase transfer reagent. Sol–gel films dopedith hydroxypyrenetrisulfonic acid (HPTS) [35,59] and thymollue [60] have also been proposed for CO2 sensing purposessee Table 3).

Gas sensors capable of detecting nitrogen dioxide in lowoncentrations find applications in a variety of industrial pro-esses, environmental and pollution control, biotechnology andioengineering. Sol–gel coatings are being used in the devel-pment of these sensors, showing promising results in termsf sensitivity and detection limit. Worsfold et al. [65] incorpo-ated an azobenzene chromophore in a sol–gel film that demon-trated to be sensitive to NO2 gas with reproducible responsend performance comparable to a Langmuir–Blodgett film ofhe same choromophore attached to a polysiloxane backbone.rant et al. [66] proposed two sol–gel-based fibre optic sen-

ors for gaseous NO2 supported on different chemistries: the

rst, based on the Saltzman reagent and fluorescent dye acri-ine orange, demonstrated sensitivity in the ppm range but wasrreversible, thus being inadequate for continuous monitoring;he second, containing a ruthenium complex, [Ru(bpy)3]Cl2,

18P.C

.A.Jeronim

oetal./Talanta

72(2007)

13–27

Table 3Optical gas sensors based on sol–gel films

Analyte Reagent Sol–gel precursors/additives Linear range/detection limit Response time Lifetime/stability Principle of detection Comments Ref.

CO NiO and Co3O4 nanocrystals TEOS + MTES; APTES (ligand) 10–500 ppm – – Transmittance (vis-NIR) – [56,57]CO2 Pyranine MTES/ETES, basic catalysis 0–20% <1 min 6 months (stored ambient) Fluorescence – [58]CO2 HPTS TEOS + PDMS + APTES 0.023% (gas)/6.6% (dissolved) 8 s (gas)/1–2 min

(dissolved)4–6 months (stored dry) Fluorescence – [35]

CO2 HPTS + Ru(dpp)3 (reference) MTES + CTAB 0.08% 20–30 s >7 weeks Fluorescence Modified atmosphere packagingapplications

[59]

CO2 Thymol blue MTMS Full range, except 0.02–0.1% 2 min – Absorption – [60]H2 NiO and Co3O4 nanocrystals TEOS + MTES; APTES (ligand) 20–850 ppm – – Transmittance (vis-NIR) – [57]H2S Thionine TEOS + MTES 0.2–100% – 6 months (stored) Absorption – [61]I2 – MTES + DMES + DPDS 100 ppb–15 ppm <15 s 3 months ATR Charge-transfer complex

between I2 and phenyl groupsof modified sol–gel

[62]

NH3 – TiO2–P2O5 mesoporous nanocompositefilm + TiO2 film

100 ppb–10 ppm 60 s, recovery: 90 s – Integrated optical polarimetricinterferometry

– [63]

NO Cobalt-tetrakis(5-sulfothienyl)porphine – – – – Absorption – [64]NO2 Azobenzene chromophores TEOS/MTES – – – Absorption – [65]NO2 Ru(bpy)3 TMOS 0.5–2% (hundreds ppm level) 15 s – Fluorescence Interference from O2 [66]NO2 Acridine orange + Saltzman reagent TMOS 0.7 ppm 50 min – FRET Irreversible [66]NO2 Porphyrin dyes MTES 176 ppb 225 s – Absorption – [67]NO2 Saltzman reagent TMOS ppb level – – Absorption – [68]O2 Ru(dpp)3 TEOS + MTES/ETES 6 ppb 5 s 6 months Fluorescence – [26,69–76]O2 Pyrene TEOS – – 300 days (stored) Fluorescence – [77]O2 Platinum octaethylporphyrin TEOS + Triton X-100 0.5–100% 5 s 5 months Phosphorescence – [78,79]O2 Cyclometallated Pt(II) complex TEOS – 10 s – Luminescence – [80]O2 Ru(bpy)3 TEOS + Triton X-100 – – – Fluorescence Regenerable with N2 [81]O2 Ru(dpp)3 – – 10 s – Luminescence – [82]O2 Ru(dpp)3 Octyl-triEOS/TEOS – – 11 months Luminescence – [83]O2 Erythrosin B TMOS, basic catalysis <9.1 mg l−1 DO – – Phosphorescence – [84]O2 Erythrosin B TEOS + fluoropolymer – – – Phosphorescence – [85]O2 Ru(bpy)3 TEOS 0–20% 20 s – Fluorescence In vivo NMR application [86]

ATR: Attenuated total reflection; DMES: dimethyldiethoxysilane; DO: dissolved oxygen; DPDS: diphenyldiethoxysilane; ETES: ethyltriethoxysilane; FRET: fluorescence resonance energy transfer; HPTS: hydroxypyrenetrisulfonic acid; MTEs: methyltriethoxysi-lane; MTMS: methyltrimethoxysilane; octyl-triEOS: n-octyltriethoxysilane; Ru(bpy)3: tris(bipyridyl)ruthenium(II); Ru(dpp)3: Ru(II)-tris(4,7-diphenyl-1,10-phenanthroline).

/ Tala

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P.C.A. Jeronimo et al.

isplayed sensitivity in the hundreds ppm range (0.5–2%), witheversibility and rapid response times. A device based on a tetra-ubstituted porphyrin dye entrapped in a sol–gel thin film waseported by Worsfold et al. [67], presenting response to a concen-ration of NO2 as low as 176 ppb at room temperature. Recently,

echery and Singh [68] developed an optical fibre-based sensorystem for selective detection of NO2 in air samples. A ppb leveletection limit was achieved by immobilizing Saltzman reagentsulfanilic acid and 1-naphtylamine) in a sol–gel film coatedn the fibre core, operating as an intrinsic sensor configuration.his device was adequate to monitor harsh environments, with

he capability of remote detection; however, unevenly distributedores of large dimensions seemed to affect sensitivity.

Most of the reported oxygen sensors are based on theuenching of fluorescence from an appropriate chemical species,uch as the transition metals photoluminescent complexes. Theuthenium complexes are widely used, due to their highlyavourable characteristics: their metal–ligand charge transfertates exhibit high emissions; they possess long unquenched life-ime and strong absorption at blue-green wavelengths. McDon-gh, McEvoy and MacCraith’s team from Dublin, Ireland, hasevoted significant research efforts to this area [23,69–76]. Theyeveloped an intrinsic optical fibre oxygen sensor (suitable foroth gas-phase and dissolved oxygen) based on sol–gel porouslms containing Ru(II)-tris(4,7-diphenyl-1,10-phenanthroline)omplex, or Ru(dpp)3, whose fluorescence is quenched in theresence of oxygen. Most of their work was focused on the opti-isation of the sol–gel microstructure, particularly in terms of

idrophobicity and porosity. This, together with the long lumi-escent period (approximately 6 �s) presented by the rutheniumomplex, enabled a highly sensitive sensor, with detection limitf 6 ppb and response time inferior to 5 s. By associating this sen-or with low cost optoelectronic components, a portable deviceas obtained, which represented a progress towards a commer-

ial instrument and made this sensor suitable for a wide scope ofpplications, from atmospheric control to river pollution mon-toring, for example [74]. More recently, the authors proposed

novel miniaturised integrated platform in order to enhancehe performance of the sensor and enable multianalyte detectionapability [76]. Ru(dpp)3 doped sol–gel film was deposited on aaveguide; changes in oxygen concentration resulted in a mod-lation of the output intensity, thereby providing the basis ofhe sensor. Multimode ridge waveguides were produced usingsoft lithography technique. Photocurable sol–gel-derived sil-

ca materials were introduced into a poly(dimethylsiloxane)ould and exposed to UV radiation. Sensor spots were then

eposited on the resultant ridge waveguides by high-resolutionin-printing. The robust and compact sensor system obtainedisplayed a resolution of less than 460 ppb over the range–9.2 ppm dissolved oxygen. The authors consider that the usef sol–gel technology was a major advantage, since it madeossible to tune the sensitivity to specific ranges through correcthoice of polymerisation conditions.

Other authors have used Ru(dpp)3 [82,83] and otheruthenium complexes, namely tris(bipyridyl)ruthenium(II)Ru(bpy)3) [81,86] for the development of novel oxygen opti-al sensors. Other luminescent oxygen-sensitive species, such

bwpe

nta 72 (2007) 13–27 19

s pyrene [77], platinum octaethylporphyrin [78,79], cyclomet-llated platinum(II) complexes [80] and erythrosine B [84,85]ave been immobilized in sol–gel coatings for detection ofxygen either dissolved or in gas-phase. All these sensors areescribed in Table 3.

.3. Sensors for ionic species

Silica thin films obtained by the sol–gel process have beensed for optical sensing of metal ions [24,88–94]. These sensors,ummarized in Table 4, are typically based on the establishmentf coloured complexes with several immobilized reagents, suchs morin, eriochrome cyanine R [88], xylenol orange [24,89],-hydroxyquinoline-5-sulfonic acid [90], porphyrin [92] and-(2-pyridylazo)resorcinol (PAR) [91,94]. The sol–gel matrixypically allows the determination of metals with very high sen-itivity, due to its dual nature: it simultaneously acts as sensingnd pre-concentration element, since it possesses a large surfacerea with controllable amounts of silanol groups; in addition,t enables the entrapment of significant amounts of indicatorolecules. The immobilized ligands must retain considerable

reedom to move or reorient, in order to be able to establishomplexes with the analyte of interest. Our team has recentlyonfirmed these findings on sol–gel films obtained by phys-cal entrapment of PAR, using a base-catalysed process. Theeveloped optical sensor, which was applied to the direct deter-ination of copper in urine [91] and to the analysis of zinc in

njectable insulins [94], exhibited a significant improvement inensitivity, as pointed above; for both applications, the apparentolar absorptivity of the PAR–metal ion complex was found

o be considerably higher than the one reported for the reactionn bulk solution, and low detection limits were obtained (seeable 4).

Besides metal ions, an optical sensor was also pro-osed for potassium sensing [95]. Ertekin and co-workersmmobilized a squaraine dye, the fluoroionophore bis[4-N-1-aza-4,7,10,13,16-pentaox acylclooctadecyl)-3,5-dihydroxy-henyl]squaraine, in sol–gel films; the sensor was fullyeversible within the dynamic range, 10−9 and 10−6 M K+, andhe response time was found to be 2 min under batch conditions.

Even though in a smaller scale, sol–gel films have alsoeen the basis for development of optical sensors for anionicpecies. A cyanide sensor was proposed by Dunuwila et al.96], prepared by encapsulation of iron(III)porphyrin in a tita-ium carboxylate thin film obtained by the sol–gel process.ince the reaction between the analyte and the colorimetric dyeas irreversible, single-use test-strips were constructed. These of sol–gel as a matrix support proved to be economicallyiable and environmentally friendly. The test-strips were sta-le over a period of 1 month and displayed a detection limitf 10 ppm, with linear response in the range 40–25,000 ppmN− and response time of 15 min. A sol–gel coating con-

aining diphenylcarbazide (DPC) and cetyltrimethylammonium

romide (CTAB) was applied to the determination of chromate,ith detection limit as low as 1 ppb [97]. However, this sensorresented a long response time, since the reaction required sev-ral steps: pre-extraction of chromate by CTAB, reduction of

20P.C

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72(2007)

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Table 4Optical sensors for determination of metals, based on indicator-doped sol–gel films

Metal Reagent Sol–gel precursors Linear range/detection limit Response time Lifetime/stability Principle of detection Comments Ref.

Al3+ Morin TMOS 4.0–2.0 ppm – – Fluorescence – [88]Bi3+ Xylenol orange TMOS 125–875 ppb/7.0 ppb 40 s, regeneration:

15 s200 determinations(4.5 h continuous use)

Absorption Coupled to flow system andapplied to pharmaceuticalanalysis

[89]

Cd2+ 8-Hydroxyquinoline-5-sulfonicacid

– <ppm – – Absorption – [90]

Cu2+ Eriochrome cyanine R TMOS 0.1 ppm – – Absorption – [88]Cu2+ PAR TEOS + APTES 5.0–80.0 ppb/3.0 ppb 100 s, regeneration:

100 s100 determinations (7 hcontinuous use); 1 year(stored at roomtemperature)

Absorption Coupled to flow system andapplied to the determinationof Cu(II) in urine

[91]

Hg2+ TPPS TMOS 1.4 ppb 15 min 1 day (continuous use) Fluorescence – [92]Hg2+ L′ TEOS/PMMA hybrid – – – Absorption HgL complex can be used for

CN− or NH3 sensing[93]

Pb2+ Xylenol orange MTES 0.01–10,400 ppm/1.04 ppb 240 s – Absorption Film coated on planarintegrated waveguide

[24]

Zn2+ PAR TEOS + APTES 5.0–25.0 ppb/2.0 ppb 100 s, regeneration:120 s

120 determinations(7.5 h continuous use);1 year (stored at roomtemperature)

Absorption Coupled to flow system andapplied to zinc analysis inslow-action insulin

[94]

L′: 2-(5-Amino-3,4-dicyano-2H-pyrrol-2-ylidene)-1,1,2-tricyanoethanide; PAR: 4-(2-pyridylazo)resorcinol; TPPS: 5,10,15,20-tetra(p-sulfonatophenyl)porphyrin.

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P.C.A. Jeronimo et al.

r(VI) to Cr(III) by DPC, and finally the formation of a purpleomplex. Jiwan and Soumillion [98] developed a halogen anionCl−, Br− and I−) sensor based on the entrapment of a flu-rophore, N-dodecyl-6-methoxyquinolinium iodide, in a silicaol–gel thin film coated on a glass substrate. The hydrophobicityf the sol–gel membrane enabled a sensor with reduced leach-ng, suitable for the measurement of chloride in the physiologicalange (100 mM/3545 ppm), and with response time of less thans. Detection limits for bromide and iodide were approximately.5 mM (599 ppm) and 0.5 mM (63.5 ppm), in that order.

.4. Sensors for determination of solvents

The sol–gel technology has been used as a resource for theevelopment of optical sensors that enable the continuous mon-toring of several solvents, with potential applications in thehemical and food industries, as well as in environmental con-rol.

Optochemical sensors for detection of water-miscible organicolvents have been referred in the literature as an alternativeo commonly employed mass spectrometry methods. Simon etl. [99] investigated the use of solvatochromic dyes (amino-N-ethylphthalimide and malachite green) immobilized in sol–gel

orous films for the development of optical sensors for determi-ation of ethanol in water. The reversible interaction with ethanolaused a change in the fluorescent properties of the indicators.ilms with malachite green were stable over a period of 5 weeksnder continuous operation. These sensors presented detectionimit of 0.6-vol% ethanol in water, with linear response in theange 0–50 vol% ethanol and response time of 2–4 min. Skrdlat al. [100] proposed an integrated sensor for determination ofsopropyl alcohol in aqueous media, using a single-mode pla-ar waveguide coated with a sol–gel film doped with methyled. This sensing device demonstrated to be potentially usefulor on-line monitoring applications, since it exhibited responsend regeneration times of less than 1 min, as well as good sen-itivity, with detection limit of 0.7% (v/v) and dynamic rangef 1–100% (v/v) isopropyl alcohol in water. Preliminary resultsndicated a stability of 6 months, stored in the dark in air. In

recent report, Hashimoto and co-workers [101] describe anptical sensor based on localized surface plasmon resonance pre-ared by the evaporation–condensation method combined withhe sol–gel technology. Thin silica film prepared by the sonogel

ethod was overcoated on silver particles; cycle performancend sensitivity of the sensor were evaluated for ethanol as wells various liquids with different refractive indices.

Films obtained by sol–gel processing have also been appliedo the construction of optical sensors for organic, non-polarolvents, both in solution and in gas phase. Lu et al. [102] devel-ped a sensor suitable for detection of low concentrations ofenzene in water, based on attenuated total reflectance-Fourierransformed infrared (ATR-FTIR) spectroscopy. A hydropho-ic mesoporous sol–gel film coated on an ATR crystal extracted

nd pre-concentrated the analyte, allowing enhanced sensitivitynd excluding the interference due to water absorption bands.allington et al. [88,103] immobilized fluorescent-labelled

-cyclodextrin in porous sol–gel coatings. The cyclodextrin

at

d

nta 72 (2007) 13–27 21

cted as a molecular receptor, containing the fluorophore ints lipophilic cavity; in the presence of small non-polar solvent

olecules, like cyclohexane or toluene, the fluorescent labelas displaced and the ensuing decrease in fluorescence inten-

ity was related to the solvent vapour concentration in the range0–100 ppm. The sensor was reversible and polar solvents suchs acetone gave no response. Stability tests were performed forweek of continuous exposure to decreasing concentrations of

olvent and 2 months storage, with good results. By means ofrather simple approach, Abdelghani et al. [104] developed anptical sensor for detection of trichloroethylene, carbon tetra-hloride, chloroform, dichloromethane, propane, butane andexane vapours, with detection limits of 0.6, 1.5, 1.7, 4, 25,0 and 5%, respectively. The sensor was based on the deposi-ion of porous TEOS films on unclad portions of optical fibres;y choosing a fixed incident angle, variations of light powerransmitted through the fibre were detected as the analyte wasorbed in the silica layer. Sorption and desorption times of the gasolecule onto the silica surface of 2 min and 2.5 min, respec-

ively, were obtained. More recently, the same authors [105]sed phenyl-modified silica films as cladding for optical fibres,btaining higher sensitivity for vapours of aromatic hydrocar-ons benzene, toluene and xylene.

.5. Other applications

Besides the more explored applications presented above,ol–gel films have been used for development of optical sensorsith promising applications in several other areas. For exam-le, Skrdla et al. [106] reported a water vapour sensor based oncombination of sol–gel processing and planar optical waveg-ide technologies. The indicator erythrosin B was entrappedn a sol–gel film, which was deposited onto a sol–gel derivedingle-mode planar waveguide. The dye exhibited an increasen absorbance in the presence of liquid or gaseous water, whichas detected as a decrease in the intensity of the light guided

n the waveguide. The sensor was able to detect water vapouroncentrations (in inert gas streams) in the low-ppm range withesponse and reversal times inferior to 1 min.

Lobnik and Cajlakovic [107] developed an optical sensoror continuous determination of dissolved hydrogen peroxide,ith possible application in industrial processes. This sensoras based on the immobilization of an indicator dye, meldolalue, in sol–gel organically modified layers. It exhibited goodelectivity and reversibility, with response time of 120 s over theoncentration range of 10−8 to 10−1 M.

Wen-xu and Jian [108] proposed the continuous monitor-ng of adriamycin in vivo using a sol–gel optical fibre sensor.he fluorescent dye 4-(N,N-dioctyl)amino-7-nitrobenz-2-oxa-,3-diazole, whose fluorescence is quenched by the antibiotic,as incorporated in a sol–gel film fixed on the tip of a 100 �mptical fibre. The carotid artery of rabbits, used as test subjects,as catheterised with a cannula housing the optical fibre, thus

llowing the continuous determination of adriamycin with detec-ion limit of 0.057 �g ml−1.

The application of organically modified sol–gel films to theevelopment of mid-infrared evanescent wave sensors for detec-

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ion of nitrated organics in aqueous media was demonstrated byanotta et al. [109,110]. Sol–gel films obtained by copolimer-zation of phenyltrimethoxysilane (PTMOS) and TMOS werepin-coated onto ZnSe attenuated total reflection waveguides.he recognition membranes obtained were successfullypplied to the determination of the organophosphate pesticidesarathion, fenitrothion, paraoxon and nitrobenzene in riverater, down to the sub-ppm concentration range. Due to their

electivity, stability (over 2 months) and reproducibility, theseensors were proposed by the authors as a potential alternative toiosensors for detection of organophosphates in environmentalnalysis.

Recently, Isobe et al. [111] used an optical fibre coatedith a porous sol–gel cladding for measurements of criticalicelle concentration (CMC) of surfactants. The method forMC detection was based on an adsorption effect in sample solu-

ion, and proved to be quite simple, accurate and cost-effective.

. Sol–gel films based optical biosensors

One of the main features of the sol–gel technology is thatt can be extended to the encapsulation of biological recogniz-ng elements (proteins, enzymes, antibodies, whole cells, etc.)112,113]. It is now well established that sol–gel immobilizediomolecules retain their structural integrity and full biologicalunctions (molecular recognition, catalysis, cell metabolism andeproduction), and are often significantly stabilized to chemicalnd thermal inactivation [114]. The ability to produce transpar-nt sol–gels with diverse chemistries and configurations, alliedo the broad applicability to the entrapment of many biomolecu-ar dopants, enabled the development of optical biosensors basedn this platform.

The prospects of using sol–gel encapsulated biomoleculesor development of improved biosensors were greatly advancedy the possibility of preparing thin films of those materials112,115]. Conventional sol–gel film processing is not suitableor encapsulation of biological agents, because the low pH andigh amounts of alcohol used lead to denaturation of most pro-eins. By using a modified protocol, in which an appropriateuffer is added after acid-catalysed hydrolysis and alcohol iseduced or replaced by sonication, a wide range of biomoleculesncapsulated in sol–gel thin films have been employed in theonstruction of optical biosensors [116–138] (Table 5).

The initial activity on optical sol–gel biosensors was centredn metalloproteins. In particular, the heme proteins are consid-red excellent model systems because they are chromophoricnd they can be readily metalated and metal-exchanged in aeversible manner; additionally, their conformation and ligandinding can be monitored via spectroscopic probing of thective centres. The first optical biosensors built with sol–geloatings were based on the affinity of haemoglobin, myoglobinr cytochrome c for CO and NO [123,124]. The results reportedlearly evidenced that sol–gels provide an ideal host matrix

or metalloproteins with variable size, showing no adverseffects on their structure or activity. Furthermore, the speed ofquilibrium response to changing redox conditions was foundo be much faster for spin-coated films than that previously

rTiw

nta 72 (2007) 13–27

eported for monoliths: 6 min instead of 15 for a thick sol–gel124].

Most work on sol–gel biosensors development has focusedn the immobilization of enzymes. Besides their unique bio-atalytic properties and specificity for a substrate or group ofubstrates, enzymes allow a wide range of analyte recogni-ion processes by using different combinations of enzymes ornzyme–transducer systems. In fact, most enzymes do not haventrinsic optical properties that undergo a change when theynteract with the analyte, so most of these sensors rely on the usef a chemical transducer; its analytical signal can be related to theoncentration of the analyte of interest. A wide variety of oxire-uctases have been immobilized in sol–gel films and employedor the monitoring of pesticides, pharmaceuticals, hydrogen per-xide, sugars, lactate, urea, cholesterol, nitrates and nitrites (seeable 5).

The most studied enzyme in the sol–gel context is glucosexidase (GOx), which mediates the air oxidation of glucoseith generation of hydrogen peroxide. Glucose oxidase is an

xtremely stable enzyme, commercially available and quitenexpensive, and known to remain active within the sol–gel

atrix [112]. Different sensing schemes based on sol–gel filmsoped with glucose oxidase have been proposed. Narang etl. [127] compared three types of configuration (physisorp-ion, microencapsulation and sol–gel sandwich) and studiedheir response profiles to glucose. Their results indicated thathe sandwich configuration (sol–gel:GOx:sol–gel) showed theost promise for future biosensor operation. Since the diffu-

ion of the analyte proceeded through the sol–gel top layer, itshickness was adjusted to 0.10 �m in order to obtain responseimes as short as 30 s. de Marcos et al. [128] immobilized glu-ose oxidase, firstly covalently bonded to a fluorescein deriva-ive, in a TMOS-based sol–gel film, as the basis of an opticalensor. During the enzymatic reaction, glucose reacted withhe labelled GOx and when the oxygen dissolved in the solu-ion was consumed, an increase in fluorescence intensity wasecorded. Wolfbeis et al. [129] developed a reversible glucoseptical biosensor by using an oxygen transducer, Ru(dpp), alongith glucose oxidase. The sensing scheme was based on theeasurement of the amount of oxygen consumed during enzy-atic action under steady-state conditions. Three different con-gurations were tested: sandwich, in which GOx was placedetween a sol–gel layer doped with Ru(dpp) and a second layerf pure sol–gel; two-layer, consisting of a sol–gel film dopedith Ru(dpp) covered with sol–gel entrapped GOx; powder,

or which GOx plus Ru(dpp)-doped sol–gel powder were dis-ersed in a sol–gel phase. Sorbitol was added to obtain moreorous sol–gel and thus improve diffusion. For all three com-inations, storage stability at 4 ◦C exceeded 4 months. Ertekint al. [130] combined glucose oxidase with a proton sensitivezlactone derivative, 4-[p-N,N-dimethylamino)benzylidene]-2-henyloxazole-5-one (DPO), in single-layer and two-layeronfigurations. The monolayer arrangement displayed faster

esponse time but considerable leaching upon prolonged use.he sensor based on the two-layer scheme was fully reversible

n the range 0.1–15 mM glucose, with response time of 40 s andorking lifetime of at least 90 days.

P.C.A

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23

Table 5Optical biosensors based on biomolecules encapsulated in sol–gel films

Immobilized biological element(+transducer)

Analyte Sol–gel precursors Linear range/detection limit Response time Lifetime/stability Principle of detection Ref.

Acetylcholinesterase(+FITC-dextran)

Paraoxon TMOS 152 ppb (30% inhibition) 30 min – Fluorescence [116]

Bacillus licheniformis, Dietziamaris, Marinobacter marinus

BOD TMOS + DiMe-DMOS (+PVA) 0.2–40 mg l−1/0.2 mg l−1 3 min (10 min recovery) 1 year (stored at 4 ◦C)a Fluorescence [117]

Bacillus subtilis (+Ru(dpp)3) BOD TMOS (+PVA-g-PVP) 0–25 mg l−1 20 min 2 months (stored in buffered GGAat 4 ◦C)

Luminescence [118]

Carbonic anhydrase (+cresol red) Acetazolamide TMOS 1.0–10.0 mM/0.2 mM 60 s 3 months (stored roomtemperature)

Absorption [119]

Cholesterol oxidase + horseradishperoxidase

Colesterol TEOS 2–10 mM 10–100 minb 8 weeks (stored roomtemperature)

Absorption [120]

Cholinesterase (+bromocresolpurple)

Carbaryl dichlorvos TEOS + PTMOS 0.11–0.8 ppm/108 ppb 12 min 3 weeks Absorption [121]

5.0–30 ppm/5.2 ppbConcanavalin-A labelled with

FITCBacterial endotoxins TEOS + APTES – – – Luminescence [122]

Cytochrome c NO and CO TMOS – – – Absorption [123]Cytochrome c NO TMOS 1–25 ppm/1 ppm 6 min – Absorption [124]Cytochrome cd1 nitrite reductase NO2

− TMOS 3.4–57 ppb/3.4 ppb 5 min Several months (stored 4 ◦C) Absorption [125]Escherichia coli (recombinant) DDT, aldicarb, malathion TMOS – >1 h Several months Luminescence [126]Glucose oxidase (GOx) Glucose TEOS 5–35 mM/0.2 mM 30 s 2 months (stored ambient) Absorption [127]GOx labelled with fluorescein Glucose TMOS 0.55–55 mM – 15 daysc Fluorescence [128]Glucose oxidase (+Ru(dpp)3) Glucose TMOS + PTMOS/MTMOS 0.1–15 mMd 50–150 se 4 months (stored 4 ◦C) Fluorescence [129]Glucose oxidase (+DPO) Glucose TEOS/TEOS + APTES 0.1–15 mM 40 s 90 days (continuous use) Fluorescence [130]Glutathione S-transferase

(+bromocresol green)Atrazine TEOS + PTMOS 2.52–125 �M/0.84 �M 200 s 1 month (continuous use) Absorption [131]

Haemoglobin NO and CO TMOS – – – Absorption [123]Horseradish peroxidase H2O2 TEOS 8 × 10−3–2 mM 30 s 2 months (continuous use) Chemiluminescence [132]Lactate dehydrogenase (+NADH) l-lactate TMOS 0.1–1.0 mM 1 min 3 weeks (stored room

temperature, dehumidifiedcabinet)

Fluorescence [133]

Lactate dehydrogenase Piruvate TEOS 0–1.5 mM/5 × 10−5 M 1 min 30 days (stored 4–10 ◦C) Absorption [134]Myoglobin NO and CO TMOS – – – Absorption [123]Nitrate reductase NO3

− TMOS 0–1.5 �M/0.125 �M – 6 months (stored 4 ◦C) Absorption [135]Pseudomonas fluorescens Naphthalene; salicylate TMOS 1.2 mg l−1; 0.5 mg l−1 – 8 months (continuous use) Bio-luminescence [136]Urease Urea TEOS 0.05 mM 10 s >6 weeks (stored 4 ◦C) Absorption [137,138]

BOD: Biochemical oxygen demand; DiMe-DMOS: dimethyldimethoxysilane; DDT: dichloro-diphenyl-trichloroethane; DPO: 4-[p-N,N-dimethylamino)benzylidene]-2-phenyloxazole-5-one; FITC: fluoresceinisothiocyanate; GGA: glucose-glutamic acid solution; MTMOS: methyltrimethoxysilane; NADH: nicotinamide adenine dinucleotide; PTMOS: phenyltrimethoxysilane; PVA: polyvinyl acetate; PVA-g-PVP:poly(vinyl alcohol)-grafted-poly(4-vinylpyridine); Ru(dpp)3: ruthenium(II)-tris(4,7-diphenyl-1,10-phenanthroline).

a Requires reactivation before use after storage.b 10 min for physically entrapped films, 30 min for physisorbed and over 100 min for microencapsulated films.c 5–6 measurements/day and then stored at 4 ◦C from 1 day to the next.d 0.1–15 mM (sandwich); 0.1–8 mM (two-layer); 0.1–4 mM (powder configuration).e 250 s (sandwich); 50 s (two-layer); 150 s (powder configuration).

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Besides glucose oxidase, there are several literature reportsn the immobilization of other enzymes within sol–gellms. Biosensors based on acetylcholinesterase (AchE) andholinesterase inhibition have been proposed for screening ofrganophosphates and carbamates, two major classes of pesti-ides that find widespread use in agriculture. Doong and Tsai116] encapsulated AchE and a pH-sensitive fluorophore, fluo-escein isothiocyanate-dextran, in a sol–gel film that could bexed on an optical fibre and integrated with a flow-througheactor for continuous monitoring. The response of the obtainediosensor to acetylcholine was reproducible in the range from.5 to 20 mM, and a 30% inhibition was achieved within 30 minhen 152 ppb paraoxon was added. Andreou and Clonis [121]eveloped a portable optical fibre biosensor for the detectionf the pesticides carbaryl and dichlorvos based on a three-layerandwich scheme: the enzyme cholinesterase was immobilizedn the outer layer, a hydrophilic modified polyvinylidenefluo-ide membrane, which was in contact with a sol–gel film dopedith bromocresol purple, deposited on an inner glass disk. The

ame sensing scheme [131] was proposed for development of aiosensor for determination of the herbicide atrazine, using thenzyme gluthatione S-transferase and bromocresol green. Wheneteriorated, the bioactive sandwich could be easily replaced onhe terminal of the probe.

Our team [119] employed carbonic anhydrase (CA) forevelopment of an optical biosensor for determination ofhe antiglaucoma agent acetazolamide, suitable for diagnosisnd pharmaceutical control purposes. The enzyme and a pH-ensitive dye, cresol red, were entrapped in overlapped sol–gellms, in a dual-layer format. CA catalysed the dehydrationf bicarbonate, which was inhibited by acetazolamide. Byollowing the colour transition of cresol red, caused by thehange of pH in the microenvironment of the sensor, the enzy-atic reaction, as well as its inhibition by acetazolamide, wereonitored. The obtained biosensor displayed good sensitivity,

educed leaching, good run-to-run stability and rapid response60 s). The immobilized enzyme showed activity retention ontorage at room temperature after a period of 3 months.

Kumar et al. [120] co-immobilized the enzymes cholesterolxidase (ChOx) and horseradish peroxidase (HRP) in a sol–gellm by means of physical adsorption, microencapsulation andhysically entrapped sandwich (sol–gel:enzyme:sol–gel) tech-iques. These systems were used for the spectrophotometricetermination of cholesterol, showing increased response timeor microencapsulated films. HRP physically immobilized inol–gel films was also used by Wang et al. [132] in order tobtain a chemiluminescent H2O2 sensor with rapid response,ood reproducibility and long lifetime.

Aylott et al. [135] demonstrated the feasibility of nitrateeductase immobilized in TMOS-based thick films as a potentialensitive and stable biosensing system for nitrate. The reductionf nitrate by nitrate reductase caused a characteristic change inhe UV–vis spectrum of the enzyme, which was quantitatively

elated with nitrate concentration in the sample. The enzymeid not leach from the sol–gel matrix and retained its activityven after a 6 months storage period. Ferreti et al. [125] encap-ulated cytochrome cd1 nitrite reductase between two sol–gel

drob

nta 72 (2007) 13–27

hin films. This structure enabled the determination of nitriten environmental waters with detection limits bellow the onesstablished by the European Union and response times of 5 min,hich was a considerable improvement when compared to the0 min response of the bulk monoliths configuration.

Sol–gel encapsulation of the enzyme lactate dehydrogenasen thin films was employed by Li et al. [133] and Ramanathan etl. [134] to obtain optical biosensors for l-lactate and piruvate,espectively. The lactate sensor, although stable for at least 3onths, was a disposable device, since it used co-immobilized

ofactor nicotinamide adenine dinucleotide (NADH), which wasot renewable.

Urease has also been entrapped in sol–gel films for develop-ent of biosensors for urea detection. Narang et al. [137] pro-

osed the sol–gel:enzyme:sol–gel sandwich architecture which,hen compared to previous designs, displayed more rapid

esponse, high storage stability, simplicity in fabrication andid not involve any chemical modification of the enzyme or these of co-dopants. Ulatowska-Jarza and Podbielska [138] com-ined urease with a pH indicator, bromothymol blue, and opticalbres.

A common way of using enzymes is through whole cellsather than the purified enzymes. This has been successfullypplied in sol–gel films-based optical biosensors for biochem-cal oxygen demand (BOD) determination, for example. Lin etl. [117] proposed a sensing film consisting of an organicallyodified silicate film embedded with tri(4,7-diphenyl-1,10-

henantroline) ruthenium(II) perclorate and three kinds ofeawater microorganisms (Bacillus licheniformis, Dietziaaris, Marinobacter marinus) immobilized on a polyvinyl

lcohol sol–gel matrix. The co-immobilized microorganismsaintained their activity even if kept up to 1 year at 4 ◦C, and the

tored sensing film could be employed for BOD measurementfter 1 day’s reactivation. Kwok et al. [118] constructed aensing device for parallel multi-sample determination of BODy immobilizing activated sludge and Bacillus subtillis onxygen sensing films placed on the bottom of glass sample vials.he microorganisms were entrapped in a sol–gel derived filmf silica and poly(vinyl alcohol)-grafted-poly(4-vinylpyridine)opolymer. The oxygen film contained Ru(II)-tris(4,7-iphenyl-1,10-phenanthroline) immobilized in a siliconeubber.

Lev and co-workers [126] demonstrated the encapsulation ofenetically engineered bioluminescent Escherichia coli reportertrains in sol–gel derived silicates. Heat shock, oxidative stress,atty acids, peroxides and genotoxicity reporting bacteria werencorporated in sol–gel films and maintained the biological prop-rties of the free culture as well as their metrological character-stics including repeatability, shelf life stability, sensitivity androad range response to a wide class of toxic compounds. Thisovel whole-cell biosensor is proposed either as a multiple-useensing element or as part of early warning devices operating inow conditions. Recently, Trogl et al. [136] immobilized Pseu-

omonas fluorescens HK44, a whole-cell bacterial reporter thatesponds to naphthalene and salicylate exposure by productionf visible light, in sol–gel films that remained mechanically sta-le for at least 8 months.

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P.C.A. Jeronimo et al.

Sol–gel materials, due to their biocompatibility and chemicalnertia, are also useful matrices for designing optical sensorsor monitoring biological species. For example, Kishen and co-orkers [139] developed an evanescent wave biosensor for theonitoring of mutans streptococci in human saliva. This sensor

mployed bromophenol blue entrapped in a porous sol–gel filmoated on the unclad portion of an optical fibre, which enabledeal time monitoring of pH variations in saliva produced by theeactivity of mutans streptococci with sucrose.

. Conclusions and trends

The significant number of applications reported, most of themuite recent, clearly illustrates the growing interest on the sol–gelrocess to develop optical sensors. There seems to be a risingwareness of the remarkable flexibility of this technology inroducing sensors that can be tailored to the needs of a spe-ific application. Optical fibre sensors based on doped sol–geloatings are easy to prepare, since the sol–gel glass is highlyompatible to silica or glass fibres. These sensors are typicallynexpensive and provide the possibility of remote sensing and inivo measurements. Through this technology, sensor arrays andensors containing multiple reagents are easily developed. Addi-ionally, since sol–gel glass is stable, inert and non-toxic, theseensors can be applied to measurements in harsh environments,n medical diagnosis and food industries. The development ofptical biosensors based on sol–gel films is also becoming moreelevant: the increasing number of applications reported in theiterature reflects the unique features of sol–gel bioencapsula-ion.

However, some critical issues are still to be considered, inrder to make mass production and commercialisation viable.significant number of sensing devices reported exhibit one orore limitations that hinder their continuous use, and some of

hem (except when specified) were not applied to real samplesr practical situations. Many of the works referred, althoughescribing optimisation and, sometimes, showing preliminaryesults, present insufficient data concerning analytical perfor-ance. It is desirable to obtain sol–gel sensors with no reagent

eaching and that can be used for a long period of time withouthanges in sensitivity and response time. Therefore, researchn this area places increasing emphasis on the critical issuesoncerning the sensors’ performance – microstructural stability,eaching, reversibility, response time, repeatability, sensitivitynd selectivity – instead of simply demonstrating the sensingotential. Once more, the same feature that first attracted atten-ion to this technology – versatility – seems to be the key onchieving this goal.

In the recent years, rapid advances have been made in improv-ng immobilization protocols and overcoming many hurdles ofol–gel technology, as shown in the reports assembled in thiseview. Novel configurations, such as miniaturised devices andntegrated sensors based on planar waveguides, are currently

mployed and provide high sensitivity, fast response and lowosts, as well as an enlarged range of possible applications.icrofabrication techniques, such as soft lithography and photo-

atternability, enable the production of new microsensors and

nta 72 (2007) 13–27 25

ioelectronic devices. Combination of sol–gel glasses with otherolymeric matrices, yielding organic–inorganic sol–gels hybridsnd composites, results in advanced materials that exhibit theexibility and functionality of organics and many of the use-ul properties of inorganics, including stability, hardness andhemical resistance. For example, the fabrication of integratedptics devices using sol–gel precursors and photocurable poly-ers coatings [140,141] allows the fabrication of a range of

ensor configurations on planar substrates, from sensor arrayso micro-total-analysis systems (�-TAS). New hybrid materi-ls constituted of organic nanocrystals embedded in sol–gellms [142] make possible to control the spatial distribution ofucleation, enabling structures with higher sensitivity and pho-ostability than dispersed dye molecules in a matrix, which givespportunity to design new 2D arrays of luminescent crystals forhemical and biological multi-sensors.

After decades of theoretical studies devoted to the full under-tanding of the sol–gel process, it is expected that the future yearsill witness a variety of new and improved sol–gel films-based

ensing applications.

cknowledgements

One of the authors (P.C.A.J.) gratefully thanks FCTFundacao para a Ciencia e Tecnologia) and FSE (III QCA)or financial support.

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